EP3500311A1 - Polymersomes à gradient de ph transmembranaire et leur utilisation dans le piégeage de l'ammoniac et de ses analogues méthylés - Google Patents
Polymersomes à gradient de ph transmembranaire et leur utilisation dans le piégeage de l'ammoniac et de ses analogues méthylésInfo
- Publication number
- EP3500311A1 EP3500311A1 EP17758637.7A EP17758637A EP3500311A1 EP 3500311 A1 EP3500311 A1 EP 3500311A1 EP 17758637 A EP17758637 A EP 17758637A EP 3500311 A1 EP3500311 A1 EP 3500311A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- polymersome
- peo
- acid
- ammonia
- polymersomes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 title claims abstract description 274
- 229920000575 polymersome Polymers 0.000 title claims abstract description 206
- 229910021529 ammonia Inorganic materials 0.000 title claims abstract description 135
- 230000002000 scavenging effect Effects 0.000 title description 12
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 133
- 229920002223 polystyrene Polymers 0.000 claims abstract description 111
- 239000003960 organic solvent Substances 0.000 claims abstract description 77
- 239000012071 phase Substances 0.000 claims abstract description 68
- 239000002253 acid Substances 0.000 claims abstract description 64
- -1 poly(styrene) Polymers 0.000 claims abstract description 56
- 208000024891 symptom Diseases 0.000 claims abstract description 38
- 238000002156 mixing Methods 0.000 claims abstract description 33
- 206010068233 Trimethylaminuria Diseases 0.000 claims abstract description 29
- 229920001400 block copolymer Polymers 0.000 claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 206010020575 Hyperammonaemia Diseases 0.000 claims abstract description 23
- 239000008346 aqueous phase Substances 0.000 claims abstract description 23
- 229920001577 copolymer Polymers 0.000 claims abstract description 23
- 239000012528 membrane Substances 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 16
- 201000010099 disease Diseases 0.000 claims abstract description 13
- 230000000699 topical effect Effects 0.000 claims abstract description 12
- 208000035475 disorder Diseases 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 62
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000003929 acidic solution Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 229920000359 diblock copolymer Polymers 0.000 claims description 4
- 150000001261 hydroxy acids Chemical class 0.000 claims description 4
- 229920000469 amphiphilic block copolymer Polymers 0.000 abstract description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- 229920000642 polymer Polymers 0.000 description 51
- 238000000338 in vitro Methods 0.000 description 50
- 239000002202 Polyethylene glycol Substances 0.000 description 34
- 238000007745 plasma electrolytic oxidation reaction Methods 0.000 description 34
- 230000002378 acidificating effect Effects 0.000 description 30
- 239000003833 bile salt Substances 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 239000000839 emulsion Substances 0.000 description 23
- 229920002988 biodegradable polymer Polymers 0.000 description 17
- 239000004621 biodegradable polymer Substances 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000009792 diffusion process Methods 0.000 description 15
- 239000002609 medium Substances 0.000 description 15
- 239000003814 drug Substances 0.000 description 14
- 239000000178 monomer Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 208000007386 hepatic encephalopathy Diseases 0.000 description 12
- 230000002209 hydrophobic effect Effects 0.000 description 12
- 239000002502 liposome Substances 0.000 description 12
- 239000008363 phosphate buffer Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 10
- 208000004926 Bacterial Vaginosis Diseases 0.000 description 9
- 208000037009 Vaginitis bacterial Diseases 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 229960003964 deoxycholic acid Drugs 0.000 description 8
- 210000001035 gastrointestinal tract Anatomy 0.000 description 8
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 8
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 208000024172 Cardiovascular disease Diseases 0.000 description 7
- 239000006071 cream Substances 0.000 description 7
- 239000006210 lotion Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000036571 hydration Effects 0.000 description 6
- 238000006703 hydration reaction Methods 0.000 description 6
- 210000000936 intestine Anatomy 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 230000004060 metabolic process Effects 0.000 description 6
- 239000007764 o/w emulsion Substances 0.000 description 6
- 238000000527 sonication Methods 0.000 description 6
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 229940093761 bile salts Drugs 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000002648 combination therapy Methods 0.000 description 5
- 230000007812 deficiency Effects 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 102000038379 digestive enzymes Human genes 0.000 description 5
- 108091007734 digestive enzymes Proteins 0.000 description 5
- 208000017169 kidney disease Diseases 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 239000012049 topical pharmaceutical composition Substances 0.000 description 5
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 5
- 210000002700 urine Anatomy 0.000 description 5
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 4
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 210000000941 bile Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 239000004205 dimethyl polysiloxane Substances 0.000 description 4
- 238000004945 emulsification Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 230000002440 hepatic effect Effects 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- 230000002727 hyperosmolar Effects 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000004987 plasma desorption mass spectroscopy Methods 0.000 description 4
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 210000001215 vagina Anatomy 0.000 description 4
- 208000007788 Acute Liver Failure Diseases 0.000 description 3
- 206010000804 Acute hepatic failure Diseases 0.000 description 3
- 206010019670 Hepatic function abnormal Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 229930193140 Neomycin Natural products 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 231100000836 acute liver failure Toxicity 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Substances [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 208000020832 chronic kidney disease Diseases 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 230000000378 dietary effect Effects 0.000 description 3
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 229960000282 metronidazole Drugs 0.000 description 3
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 3
- 229960004927 neomycin Drugs 0.000 description 3
- CXQXSVUQTKDNFP-UHFFFAOYSA-N octamethyltrisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000344 soap Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 229920000428 triblock copolymer Polymers 0.000 description 3
- 239000001124 (E)-prop-1-ene-1,2,3-tricarboxylic acid Substances 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- RLHGFJMGWQXPBW-UHFFFAOYSA-N 2-hydroxy-3-(1h-imidazol-5-ylmethyl)benzamide Chemical compound NC(=O)C1=CC=CC(CC=2NC=NC=2)=C1O RLHGFJMGWQXPBW-UHFFFAOYSA-N 0.000 description 2
- JLBJTVDPSNHSKJ-UHFFFAOYSA-N 4-Methylstyrene Chemical compound CC1=CC=C(C=C)C=C1 JLBJTVDPSNHSKJ-UHFFFAOYSA-N 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 2
- 208000002467 Acute-On-Chronic Liver Failure Diseases 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- ODBLHEXUDAPZAU-ZAFYKAAXSA-N D-threo-isocitric acid Chemical compound OC(=O)[C@H](O)[C@@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-ZAFYKAAXSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 206010017943 Gastrointestinal conditions Diseases 0.000 description 2
- ODBLHEXUDAPZAU-FONMRSAGSA-N Isocitric acid Natural products OC(=O)[C@@H](O)[C@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-FONMRSAGSA-N 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- 241001082241 Lythrum hyssopifolia Species 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 241000220317 Rosa Species 0.000 description 2
- 101000953909 Streptomyces viridifaciens Isobutylamine N-hydroxylase Proteins 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 241000906446 Theraps Species 0.000 description 2
- 229940091181 aconitic acid Drugs 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000010560 atom transfer radical polymerization reaction Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- GTZCVFVGUGFEME-IWQZZHSRSA-N cis-aconitic acid Chemical compound OC(=O)C\C(C(O)=O)=C\C(O)=O GTZCVFVGUGFEME-IWQZZHSRSA-N 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 108010057167 dimethylaniline monooxygenase (N-oxide forming) Proteins 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 210000003608 fece Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 238000001631 haemodialysis Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000000322 hemodialysis Effects 0.000 description 2
- 229920001600 hydrophobic polymer Polymers 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000008011 inorganic excipient Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 2
- 229960000511 lactulose Drugs 0.000 description 2
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000008012 organic excipient Substances 0.000 description 2
- 239000008385 outer phase Substances 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 229920000515 polycarbonate Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- NZCRJKRKKOLAOJ-XRCRFVBUSA-N rifaximin Chemical compound OC1=C(C(O)=C2C)C3=C4N=C5C=C(C)C=CN5C4=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O NZCRJKRKKOLAOJ-XRCRFVBUSA-N 0.000 description 2
- 229960003040 rifaximin Drugs 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- ODBLHEXUDAPZAU-UHFFFAOYSA-N threo-D-isocitric acid Natural products OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 2
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 2
- 150000003628 tricarboxylic acids Chemical class 0.000 description 2
- XLDZZWCVODPLFF-UHFFFAOYSA-N (1-methoxy-2-phenylethenoxy)methylbenzene Chemical compound C=1C=CC=CC=1C=C(OC)OCC1=CC=CC=C1 XLDZZWCVODPLFF-UHFFFAOYSA-N 0.000 description 1
- QLSHRSPPXSAGTR-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 4-ethenylbenzoate Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1OC(=O)C1=CC=C(C=C)C=C1 QLSHRSPPXSAGTR-UHFFFAOYSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 description 1
- PHQFMPNZCIHSPC-UHFFFAOYSA-N 1,3,5-tris(chloromethyl)-2,4,6-trimethylbenzene Chemical group CC1=C(CCl)C(C)=C(CCl)C(C)=C1CCl PHQFMPNZCIHSPC-UHFFFAOYSA-N 0.000 description 1
- ZZHIDJWUJRKHGX-UHFFFAOYSA-N 1,4-bis(chloromethyl)benzene Chemical compound ClCC1=CC=C(CCl)C=C1 ZZHIDJWUJRKHGX-UHFFFAOYSA-N 0.000 description 1
- SLBOQBILGNEPEB-UHFFFAOYSA-N 1-chloroprop-2-enylbenzene Chemical compound C=CC(Cl)C1=CC=CC=C1 SLBOQBILGNEPEB-UHFFFAOYSA-N 0.000 description 1
- XIRPMPKSZHNMST-UHFFFAOYSA-N 1-ethenyl-2-phenylbenzene Chemical group C=CC1=CC=CC=C1C1=CC=CC=C1 XIRPMPKSZHNMST-UHFFFAOYSA-N 0.000 description 1
- QTGRTPLTNPCDLH-UHFFFAOYSA-N 1-ethenyl-2-phenylbenzene trimethyl(1-phenylprop-2-enyl)azanium Chemical group C[N+](C)(C)C(C=C)c1ccccc1.C=Cc1ccccc1-c1ccccc1 QTGRTPLTNPCDLH-UHFFFAOYSA-N 0.000 description 1
- UVHXEHGUEKARKZ-UHFFFAOYSA-N 1-ethenylanthracene Chemical compound C1=CC=C2C=C3C(C=C)=CC=CC3=CC2=C1 UVHXEHGUEKARKZ-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PWESSVUYESFKBH-UHFFFAOYSA-N 2,2-dimethoxyethenylbenzene Chemical compound COC(OC)=CC1=CC=CC=C1 PWESSVUYESFKBH-UHFFFAOYSA-N 0.000 description 1
- YOCIJWAHRAJQFT-UHFFFAOYSA-N 2-bromo-2-methylpropanoyl bromide Chemical compound CC(C)(Br)C(Br)=O YOCIJWAHRAJQFT-UHFFFAOYSA-N 0.000 description 1
- SBYMUDUGTIKLCR-UHFFFAOYSA-N 2-chloroethenylbenzene Chemical compound ClC=CC1=CC=CC=C1 SBYMUDUGTIKLCR-UHFFFAOYSA-N 0.000 description 1
- XUDBVJCTLZTSDC-UHFFFAOYSA-N 2-ethenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C=C XUDBVJCTLZTSDC-UHFFFAOYSA-N 0.000 description 1
- FZHNODDFDJBMAS-UHFFFAOYSA-N 2-ethoxyethenylbenzene Chemical compound CCOC=CC1=CC=CC=C1 FZHNODDFDJBMAS-UHFFFAOYSA-N 0.000 description 1
- KBKNKFIRGXQLDB-UHFFFAOYSA-N 2-fluoroethenylbenzene Chemical compound FC=CC1=CC=CC=C1 KBKNKFIRGXQLDB-UHFFFAOYSA-N 0.000 description 1
- BTOVVHWKPVSLBI-UHFFFAOYSA-N 2-methylprop-1-enylbenzene Chemical compound CC(C)=CC1=CC=CC=C1 BTOVVHWKPVSLBI-UHFFFAOYSA-N 0.000 description 1
- PIAOLBVUVDXHHL-UHFFFAOYSA-N 2-nitroethenylbenzene Chemical compound [O-][N+](=O)C=CC1=CC=CC=C1 PIAOLBVUVDXHHL-UHFFFAOYSA-N 0.000 description 1
- FMFHUEMLVAIBFI-UHFFFAOYSA-N 2-phenylethenyl acetate Chemical compound CC(=O)OC=CC1=CC=CC=C1 FMFHUEMLVAIBFI-UHFFFAOYSA-N 0.000 description 1
- VSRLHPGHDYXVQT-UHFFFAOYSA-N 2-phenylhex-2-en-3-ylbenzene Chemical compound C=1C=CC=CC=1C(CCC)=C(C)C1=CC=CC=C1 VSRLHPGHDYXVQT-UHFFFAOYSA-N 0.000 description 1
- KXYAVSFOJVUIHT-UHFFFAOYSA-N 2-vinylnaphthalene Chemical compound C1=CC=CC2=CC(C=C)=CC=C21 KXYAVSFOJVUIHT-UHFFFAOYSA-N 0.000 description 1
- HKADMMFLLPJEAG-UHFFFAOYSA-N 3,3,3-trifluoroprop-1-enylbenzene Chemical compound FC(F)(F)C=CC1=CC=CC=C1 HKADMMFLLPJEAG-UHFFFAOYSA-N 0.000 description 1
- DXIJHCSGLOHNES-UHFFFAOYSA-N 3,3-dimethylbut-1-enylbenzene Chemical compound CC(C)(C)C=CC1=CC=CC=C1 DXIJHCSGLOHNES-UHFFFAOYSA-N 0.000 description 1
- IWTYTFSSTWXZFU-UHFFFAOYSA-N 3-chloroprop-1-enylbenzene Chemical compound ClCC=CC1=CC=CC=C1 IWTYTFSSTWXZFU-UHFFFAOYSA-N 0.000 description 1
- QMYGFTJCQFEDST-UHFFFAOYSA-N 3-methoxybutyl acetate Chemical group COC(C)CCOC(C)=O QMYGFTJCQFEDST-UHFFFAOYSA-N 0.000 description 1
- ZTHJQCDAHYOPIK-UHFFFAOYSA-N 3-methylbut-2-en-2-ylbenzene Chemical compound CC(C)=C(C)C1=CC=CC=C1 ZTHJQCDAHYOPIK-UHFFFAOYSA-N 0.000 description 1
- CFYIUBWVKZQDOG-UHFFFAOYSA-N 4-[[2-[[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-4-oxobutanoic acid Chemical compound C=1C=C([N+]([O-])=O)C=CC=1NC(=O)C(NC(=O)CNC(=O)CNC(=O)CCC(=O)O)CC1=CC=CC=C1 CFYIUBWVKZQDOG-UHFFFAOYSA-N 0.000 description 1
- DTGDMPJDZKDHEP-UHFFFAOYSA-N 4-ethenylbicyclo[4.2.0]octa-1(6),2,4-triene Chemical compound C=CC1=CC=C2CCC2=C1 DTGDMPJDZKDHEP-UHFFFAOYSA-N 0.000 description 1
- VHJFWJXYEWHCGD-UHFFFAOYSA-N 4-nonyl-2-(4-nonylpyridin-2-yl)pyridine Chemical group CCCCCCCCCC1=CC=NC(C=2N=CC=C(CCCCCCCCC)C=2)=C1 VHJFWJXYEWHCGD-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Natural products CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 235000011331 Brassica Nutrition 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229940121727 Glutaminase inhibitor Drugs 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- ASJUVHZRHDYVKS-UHFFFAOYSA-N N-methyl-N'-(3-phenylprop-2-enyl)ethane-1,2-diamine Chemical compound CNCCNCC=CC1=CC=CC=C1 ASJUVHZRHDYVKS-UHFFFAOYSA-N 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 229920000361 Poly(styrene)-block-poly(ethylene glycol) Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010042458 Suicidal ideation Diseases 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108010046334 Urease Proteins 0.000 description 1
- IXUZXIMQZIMPSQ-ZBRNBAAYSA-N [(4s)-4-amino-4-carboxybutyl]azanium;(2s)-2-amino-4-hydroxy-4-oxobutanoate Chemical compound OC(=O)[C@@H](N)CCC[NH3+].[O-]C(=O)[C@@H](N)CC(O)=O IXUZXIMQZIMPSQ-ZBRNBAAYSA-N 0.000 description 1
- YMOONIIMQBGTDU-VOTSOKGWSA-N [(e)-2-bromoethenyl]benzene Chemical compound Br\C=C\C1=CC=CC=C1 YMOONIIMQBGTDU-VOTSOKGWSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000037358 bacterial metabolism Effects 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 239000003012 bilayer membrane Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 150000005693 branched-chain amino acids Chemical class 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- LCQLHJZYVOQKHU-VKHMYHEASA-N carglumic acid Chemical compound NC(=O)N[C@H](C(O)=O)CCC(O)=O LCQLHJZYVOQKHU-VKHMYHEASA-N 0.000 description 1
- 229960002779 carglumic acid Drugs 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 229940099898 chlorophyllin Drugs 0.000 description 1
- 235000019805 chlorophyllin Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000009295 crossflow filtration Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000020805 dietary restrictions Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- UMFWLUTUYFDZNQ-UHFFFAOYSA-N diphenyl(2-phenylethenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C=CC1=CC=CC=C1 UMFWLUTUYFDZNQ-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 229960002815 glycerol phenylbutyrate Drugs 0.000 description 1
- ZSDBFLMJVAGKOU-UHFFFAOYSA-N glycerol phenylbutyrate Chemical compound C=1C=CC=CC=1CCCC(=O)OCC(OC(=O)CCCC=1C=CC=CC=1)COC(=O)CCCC1=CC=CC=C1 ZSDBFLMJVAGKOU-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015978 inherited metabolic disease Diseases 0.000 description 1
- 239000008384 inner phase Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 125000003010 ionic group Chemical group 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 235000019626 lipase activity Nutrition 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- KDYPRVCJDOSOQD-UHFFFAOYSA-N n-benzyl-2-methylprop-1-en-1-amine Chemical compound CC(C)=CNCC1=CC=CC=C1 KDYPRVCJDOSOQD-UHFFFAOYSA-N 0.000 description 1
- PZUGJLOCXUNFLM-UHFFFAOYSA-N n-ethenylaniline Chemical compound C=CNC1=CC=CC=C1 PZUGJLOCXUNFLM-UHFFFAOYSA-N 0.000 description 1
- ALEGPCQGKQHWJG-UHFFFAOYSA-N n-prop-1-en-2-ylaniline Chemical compound CC(=C)NC1=CC=CC=C1 ALEGPCQGKQHWJG-UHFFFAOYSA-N 0.000 description 1
- 230000003557 neuropsychological effect Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 229960002460 nitroprusside Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- SFBTTWXNCQVIEC-UHFFFAOYSA-N o-Vinylanisole Chemical compound COC1=CC=CC=C1C=C SFBTTWXNCQVIEC-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 108010049063 ornithylaspartate Proteins 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 208000030613 peripheral artery disease Diseases 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920001559 poly(2-methyloxazoline)-block-poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000006041 probiotic Substances 0.000 description 1
- 230000000529 probiotic effect Effects 0.000 description 1
- 235000018291 probiotics Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229920013730 reactive polymer Polymers 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000009094 second-line therapy Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- 229960002232 sodium phenylbutyrate Drugs 0.000 description 1
- VPZRWNZGLKXFOE-UHFFFAOYSA-M sodium phenylbutyrate Chemical compound [Na+].[O-]C(=O)CCCC1=CC=CC=C1 VPZRWNZGLKXFOE-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000000000 tetracarboxylic acids Chemical class 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000037999 tubulointerstitial fibrosis Diseases 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 238000005353 urine analysis Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to transmembrane pH-gradient polymersomes and their use in the scavenging of ammonia and its methylated analogs (e.g., trimethylamine (TMA)). More specifically, the present invention is concerned with polymersomes comprising non-biodegradable amphiphilic block-copolymers and their enteral (e.g., oral) or topical use in the scavenging of ammonia and/or its methylated analogs (e.g., TMA) for the treatment of e.g., hyperammonemia, trimethylaminuria, cardiovascular and/or chronic kidney diseases.
- TMA trimethylamine
- Ammonia (NH3) and its methylated analogs possess similar physicochemical properties (e.g., low molecular weight, similar pKa and logP, etc.). They are both mainly produced in the gastrointestinal tract and their presence in excess in the body is associated with various disorders and symptoms thereof.
- Ammonia is a neurotoxic endogenous metabolite which accumulates in patients suffering from impaired liver function (e.g., due to liver cirrhosis, acute liver failure, portosystemic shunting, inborn errors of ammonia metabolism) (Matoori and Leroux ADDR 2015; 90:55-68).
- hepatic encephalopathy recommends as first- and second-line therapy for hepatic encephalopathy the non-absorbable disaccharide lactulose (a commonly used laxative) and the antibiotic rifaximin (e.g., XifaxanTM) which tackle the generation and absorption of colonic ammonia in a rather unspecific manner (Vilstrup et al. supra).
- Both of these orally available therapies fail to control the symptoms and progression of hepatic encephalopathy in a large fraction of the patient population and many patients under these therapies suffer from adverse reactions such as diarrhea (Vilstrup et al. supra; Rose Clinical Pharmacology & Therapeutics 2012; 92:321-331 ; Leevy et al., Dig Dis Sci 2007; Mullen et al. Clin Gastroenterol Hepatol 2014; 12: 1390-1397.e2).
- AST-120 Orally administered spherical carbon adsorbent (AST-120, Kremezin®) were also disclosed for sequestering ammonia and improving hyperammonemia-associated symptoms in an animal model of hepatic encephalopathy (Bosoi et al. Hepatology 2011 ; 53: 1995-2002).
- ammonia adsorbs to AST-120 microparticles in the gut and is subsequently excreted via the feces.
- AST-120 treatment did not lead to clinical improvement in neuropsychological symptoms, probably due to the insufficient binding of ammonia (Bajaj et al. J.
- Carbon adsorbents are known to bind to a variety of compounds and bear the risk of interfering with important endogenous or exogenous substances (Schulman et al. Am J Kidney Dis 2006; 47:565-577; Neuvonen and Elonen Eur J Clin Pharmacol 1980; 17:51-57; Neuvonen and Olkkola Med Toxicol 1988; 3:33-58).
- ammonia-removing treatment strategies based on extracorporeal approaches are not ideal because they are invasive and mainly suited to treat severe acute hyperammonemic episodes.
- An ideal treatment for patients suffering from hyperammonemia-induced hepatic encephalopathy would be an enteral treatment (e.g., oral), potent and selective in ammonia uptake, and stable in the harsh environment of the gastrointestinal tract.
- enteral treatment e.g., oral
- potent and selective in ammonia uptake and stable in the harsh environment of the gastrointestinal tract.
- Trimethylamine (N(CH3)3) is a tertiary amine which is generated in the intestine by the bacterial metabolism of dietary substances (e.g., choline, carnitine, lecithin) (Wang Z et al. (2011). Nature 472(7341), 57-63; Wise PM et al. (2011). The American journal of medicine 124(11), 1058-1063). TMA is subsequently oxidized by flavin monooxygenase 3 into the non-odorous trimethylamine-N-oxide (TMAO) in the liver (Yeung CK et al. (2007). Archives of biochemistry and biophysics, 464(2), 251-259). TMA and its metabolite TMAO are involved in the etiology of several diseases.
- TMAO trimethylamine-N-oxide
- Trimethylaminuria also known as fish odor syndrome
- Trimethylaminuria is an autosomal recessive disorder linked to flavin monooxygenase 3 deficiency (Yeung et al., supra).
- Patients suffering from trimethylaminuria generally present with malodor (often associated with rotten fish) due to elevated amounts of TMA in bodily fluids (urine, sweat) and expired air (Wise et al., supra).
- the diagnosis of trimethylaminuria is usually based on a dietary choline challenge and subsequent urine analysis of TMA and TMAO (Wise et al., supra).
- the perceptible smell mainly stems from the skin surface and varies depending on the diet (Wise et al., supra). Due to their malodor, trimethylaminuria patients often suffer from psychological symptoms (e.g., depression, suicidal tendencies) and social isolation (Todd WA (1979). The Journal of pediatrics, 94(6), 936
- TMAO levels were also associated with an increased risk of cardiovascular disease and chronic kidney disease (Tang WW et al. (2013). New England Journal of Medicine 368(17), 1575-1584; Tang WW et al. (2015). Circulation research 116(3), 448-455); and the inhibition of gut microbial TMA production led to a reduction in atherosclerotic lesions (Wang Z et al. (2015). Cell 163(7), 1585-1595).
- TMA was found to be a contributor to the unpleasant smell in bacterial vaginosis
- Trimethylaminuria treatments In the treatment of trimethylaminuria, dietary restrictions such as avoiding Brassica vegetables and carnitine-, choline-, or lecithin-rich foods are recommended to decrease the malodor (Cashman JR et al. (1999) ln-vitro and in-vivo studies inhibition of human flavin-containing monooxygenase form 3 (FM03) in the presence of dietary indoles. Biochem Pharmacol 58, 1047-1055; Cashman JR et al. (2003). Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FM03) related to trimethylaminuria.
- the ammonia methylated analog dimethylamine (DMA) shares similar physicochemical properties as TMA and ammonia and is produced in the Gl tract. It is a precursor of a known carcinogen.
- This invention describes the composition, preparation and use of transmembrane pH-gradient polymersomes for ammonia and its methylated analogs (e.g., TMA) detoxification/scavenging via the enteral (e.g., oral) route and the topical route.
- the polymersomes of the present invention strongly sequester ammonia and its methylated analogs (e.g., TMA) in simulated gastrointestinal fluids and resist to this harsh environment.
- the polymersomes of the present invention strongly sequester TMA in emulsions (e.g., topical formulations such as lotions and creams).
- the polymersomes of the present invention were shown to exhibit their sequestering properties when diluted in a medium mimicking the conditions encountered in the intestine, contrarily to transmembrane pH-gradient liposomes for instance (see e.g., Example 1).
- the stability and efficacy of the polymersomes in the gastrointestinal environment was demonstrated in Examples below by showing the uptake of ammonia under variable simulated gastrointestinal conditions (high bile salt concentrations (Examples 6-8 and 13), hypo- and hyperosmolarity (Example 9), presence of digestive enzymes (Example 10) and high cation concentrations (Example 11)).
- the stability and efficacy of the polymersomes were also demonstrated in oil in water (o/w) emulsions corresponding to e.g., a topical formulation (Example 13).
- This invention describes for example polymersomes composed of non-biodegradable amphiphilic block-copolymers (e.g. poly (styrene)-b-poly (ethylene oxide) (PS-b-PEO, also known as poly (styrene)-b-poly (ethylene glycol), PS-b-PEG)).
- non-biodegradable amphiphilic block-copolymers e.g. poly (styrene)-b-poly (ethylene oxide) (PS-b-PEO, also known as poly (styrene)-b-poly (ethylene glycol), PS-b-PEG)
- a polymersome (a) the membrane of which comprises a block copolymer of a hydrophobic uncharged nonbiodegradable polymer and a hydrophilic uncharged non-biodegradable polymer as defined herein, wherein the hydrophobic uncharged non-biodegradable polymer / hydrophilic uncharged and non-biodegradable polymer molecular weight ratio is higher than 1.0 and lower than 4.0 (e.g., higher than 1.0 and lower than 3.0); and (b) the core of which encloses an acid.
- a polymersome comprising (a) a membrane, which comprises a block copolymer of a hydrophobic uncharged nonbiodegradable polymer and a hydrophilic uncharged non-biodegradable polymer as defined herein, wherein the hydrophobic uncharged non-biodegradable polymer / hydrophilic uncharged and non-biodegradable polymer molecular weight ratio is higher than 1.0 and lower than 4.0 (e.g., higher than 1.0 and lower than 3.0); and (b) a core which encloses an acid.
- a polymersome consisting of (a) a membrane, which comprises a block copolymer of a hydrophobic uncharged nonbiodegradable polymer and a hydrophilic uncharged non-biodegradable polymer as defined herein, wherein the hydrophobic uncharged non-biodegradable polymer / hydrophilic uncharged and non-biodegradable polymer molecular weight ratio is higher than 1.0 and lower than 4.0 (e.g., higher than 1.0 and lower than 3.0); and (b) a core which encloses an acid.
- a polymersome (a) the membrane of which comprises a block copolymer of poly(styrene) (PS) and polyethylene oxide) (PEO), wherein the PS/PEO molecular weight ratio is higher than 1.0 and lower than 4.0 (e.g., higher than 1.0 and lower than 3.0); and (b) the core of which encloses an acid.
- PS poly(styrene)
- PEO polyethylene oxide
- a polymersome comprising (a) a membrane, which comprises a block copolymer of poly(styrene) (PS) and polyethylene oxide) (PEO), wherein the PS/PEO molecular weight ratio is higher than 1.0 and lower than 4.0 (e.g., higher than 1.0 and lower than 3.0); and (b) the core of which encloses an acid.
- PS poly(styrene)
- PEO polyethylene oxide
- a polymersome consisting of (a) a membrane, which comprises a block copolymer of poly(styrene) (PS) and polyethylene oxide) (PEO), wherein the PS/PEO molecular weight ratio is higher than 1.0 and lower than 4.0 (e.g., higher than 1.0 and lower than 3.0); and (b) the core of which encloses an acid.
- PS poly(styrene)
- PEO polyethylene oxide
- the polymersomes of the present invention may be crosslinked or not.
- a polymersome (a) the membrane of which consists of a block copolymer of poly(styrene) (PS) and polyethylene oxide) (PEO), wherein the PS/PEO molecular weight ratio is higher than 1.0 and lower than 4.0 (e.g., higher than 1.0 and lower than 3.0); and (b) the core of which encloses an acid.
- PS poly(styrene)
- PEO polyethylene oxide
- a polymersome comprising (a) a membrane, which consists of a block copolymer of poly(styrene) (PS) and polyethylene oxide) (PEO), wherein the PS/PEO molecular weight ratio is higher than 1.0 and lower than 4.0 (e.g., higher than 1.0 and lower than 3.0); and (b) a core which encloses an acid.
- a membrane which consists of a block copolymer of poly(styrene) (PS) and polyethylene oxide) (PEO), wherein the PS/PEO molecular weight ratio is higher than 1.0 and lower than 4.0 (e.g., higher than 1.0 and lower than 3.0); and
- a core which encloses an acid.
- a polymersome consisting of (a) a membrane, which consists of a block copolymer of poly(styrene) (PS) and polyethylene oxide) (PEO), wherein the PS/PEO molecular weight ratio is higher than 1.0 and lower than 4.0 (e.g., higher than 1.0 and lower than 3.0); and (b) a core which encloses an acid.
- PS poly(styrene)
- PEO polyethylene oxide
- the block copolymer is a di block copolymer.
- the acid is in a concentration that produces a pH between 1 and 6, preferably between 2 and 5, more preferably between 2 and 4, when the polymersome is hydrated.
- the acid is within an aqueous acidic solution.
- the pH within the aqueous acidic solution is between 1 and 6, preferably between 2 and 5, more preferably between 2 and 4.
- the acid is (i) a hydroxy acid such as citric acid, isocitric acid, malic acid, tartaric acid or lactic acid; (ii) a small chain fatty acid such as acetic acid; (lii) a sugar acid such as uronic acid; (iv) a dicarboxylic acid such as malonic acid; (v) a tricarboxylic acid such as propane- ,2,3-tricarboxylic acid or aconitic acid; (vi) a tetracarboxylic acid such as 1,2,3,4- butanetetracarboxylic acid; (vii) a pentacarboxy!ic acid such as 1 ,2,3,4,5-pentanepentaearboxylic acid; (viii) a polymeric po!y(carboxy!ic acid) such as po!y(acryiic acid) or poiy(methacrylic acid); (ix) a polya hydroxy acid such as citric acid, isocitric
- the polymersome of the present invention is prepared by a method comprising mixing an organic solvent containing the copolymer with an aqueous phase containing the acid, in another specific embodiment of the polymersome of the present invention, the organic solvent is water immiscible or partially water miscible.
- the polymersome core further encloses ammonia.
- the polymersome core further encloses ammonia or its methylated analog, the methylated analog being preferably T A.
- the poiymersome core further encloses an ammonia methylated analog (e.g., TMA).
- composition comprising the polymersome of the present invention, and at least one pharmaceutically acceptable excipient.
- the composition in liquid, or solid form. In another specific embodiment of the composition of the present invention, the composition is in liquid, semi solid or solid form.
- polymersome of the present invention or the composition of the present invention for enteral use.
- polymersome of the present Invention or the composition of the present Invention for enteral use or topical use.
- the poiymersome of the present invention or the composition of the present invention for topical use.
- the polymersome of the present invention or the composition of the present invention is for use in scavenging ammonia.
- the polymersome of the present invention or the composition of the present invention is for use in scavenging an ammonia methylated analog (e.g., T A).
- an ammonia methylated analog e.g., T A
- the polymersome or composition of the present invention for use in the treatment of an ammonia or ammonia methylated analog-associated disease or disorder, or a symptom thereof, and preferably hyperammonemia or trimethylaminuria.
- the polymersome of the present invention or the composition of the present invention is for use in the treatment of hyperammonemia.
- the polymersome of the present invention or the composition of the present invention is for use in the treatment of trimethylaminuria or a symptom thereof or a TMA-associated cardiovascular disease or a symptom thereof or a TMA-associated kidney disease or a symptom thereof or TMA- associated bacterial vaginosis or a symptom thereof, in a subject in need thereof.
- the trimethylaminuria symptom and/or bacterial vaginosis symptom is malodor (from e.g., skin and/or urine and/or expired air and/or vagina).
- a method of using the polymersome of the invention or the composition of the invention comprising (e.g., enterally or topically) administering the polymersome or composition to a subject in need thereof.
- a use of the polymersome of the invention or the composition of the invention as a medicament there is provided.
- the above method(s) or use(s) is for (of for the manufacture of a medicament for) scavenging ammonia.
- the above method(s) or use(s) is tor (of for the manufacture of a medicament for) scavenging an ammonia methylated analog (e.g., TMA) in a subject in need thereof.
- an ammonia methylated analog e.g., TMA
- the above method(s) or use(s) is for (of for the manufacture of a medicament for) the treatment of an ammonia or ammonia methylated analog-associated disease or disorder, or a symptom thereof, and preferably hyperammonemia or trimethylaminuria, more preferably hyperammonemia, in a subject in need thereof
- the above method(s) or use(s) is for (of for the manufacture of a medicament for) the treatment of trimethylaminuria or a symptom thereof or a TMA-associated cardiovascular disease or a symptom thereof or a TMA-associated kidney disease or a symptom thereof or TMA- associated bacterial vaginosis or a symptom thereof, in a subject in need thereof.
- the trimethylaminuria symptom and/or bacterial vaginosis symptom is malodor (from e.g., skin and/or urine and/or expired air and/or vagina).
- a method of making the polymersome of the present invention comprising: (a) dissolving the block copolymer of PS and PEO in an organic solvent, preferably a water-immiscible or partially water-miscible organic solvent, to form a copolymer- containing organic phase; (b) mixing the copolymer-containing organic solvent phase with an aqueous phase containing the acid so as to form the polymersome; and (c) removing the organic solvent.
- an organic solvent preferably a water-immiscible or partially water-miscible organic solvent
- the aqueous phase comprises between 50 and 700 m!VI of acid.
- the present invention provides a kit comprising the above-mentioned polymersomes or compositions and instructions to use the polymersomes or compositions for scavenging ammonia in a subject in need thereof.
- the present invention provides a kit comprising the above-mentioned polymersomes or compositions and instructions to use the polymersomes or compositions for treating hyperammonemia in a subject in need thereof.
- the present invention provides a kit comprising the above-mentioned polymersomes or compositions and instructions to use the polymersomes or compositions for scavenging an ammonia methylated analog (e.g., TMA).
- an ammonia methylated analog e.g., TMA
- the present invention provides a kit comprising the above-mentioned polymersomes or compositions and instructions to use the polymersomes or compositions for treating trimethylaminuria or a symptom thereof or a TMA-associated cardiovascular disease or a symptom thereof or a TMA- associated kidney disease or a symptom thereof or TMA-associated bacterial vaginosis or a symptom thereof, in a subject in need thereof.
- the trimethylaminuria symptom and/or bacterial vaginosis symptom is malodor (from e.g., skin and/or urine and/or expired air and/or vagina).
- FIG. 3 is a graph showing the in vitro ammonia uptake of transmembrane pH-gradient PMOXA-b-
- the present invention encompasses polymersomes possessing transmembrane pH-gradient to capture ammonia and/or its methylated analogs (e.g., TMA), compositions comprising the polymersomes, processes for making the polymersomes and the use of these polymersomes and compositions.
- TMA methylated analogs
- Polymersomes are vesicles, the bilayer membrane of which is assembled from synthetic copolymers. They have mean diameters ranging from 50 nm to 100 ⁇ or more, in a specific embodiment, ranging from 100 nm to 40 ⁇ , as determined by laser diffraction. Although tested polymersomes of the present invention having mean diameters varying between 100 nm to 40 ⁇ were able to effectively encapsulate ammonia, there is no reason to believe that polymersomes with a diameter larger than 40 ⁇ could not also be effective.
- Polymersomes of the present invention comprise non-biodegradable amphiphilic block copolymers and are prepared using an organic solvent.
- the mechanism of action of the present invention is based on the pH gradient across the polymersome membrane.
- the acidic agent contained in the aqueous polymersome core possesses a pH different (lower than) from the physiological pH in the intestine and the skin.
- ammonia and its methylated analogs e.g., TMA
- TMA ammonia and its methylated analogs
- ammonia and TMA are mainly existing in their protonated state at the pH of the intestine and skin, there is always a small fraction in its non-ionized state. This fraction can diffuse in the polymersomes and be trapped in their protonated state inside the polymersomes, which in turn displaces the equilibrium, bringing more ammonia and TMA inside the vesicles.
- transmembrane pH gradient to capture ammonia and/or its methylated analogs » therefore refers to the ability of the polymersomes of the present invention to sequester ammonia (and/or its methylated analogs) when diluted in a medium mimicking the conditions encountered in the intestine or on the skin.
- ammonia methylated analogs refers, without being so limited, to TMA, and DMA. In a specific embodiment, it refers to TMA.
- Block copolymers are macromoiecuies comprising connected monomeric units.
- the monomeric units may be of a single type (homogeneous), or a variety of types (heterogeneous).
- a copolymer made of a sequence of two or more monomers of a single type (a block) covalently joined to two or more monomers of another type (another block) is called a block copolymer.
- a copolymer made of two block types covalently joined together is called a diblock, of three block types, is called a triblock, etc.
- Block copolymers can comprise, as a result of the specific synthesis used to generate them, different end groups.
- Polymersomes of the present invention comprise block copolymers.
- the block copolymers of the present invention are diblock or triblock copolymers. These block copolymers are amphiphilic and are formed of at least two polymers, namely an aromatic highly hydrophobic polymer (e.g. poly(styrene)) and a hydrophilic uncharged and non-biodegradable polymer.
- the block copolymer is a diblock copolymer (e.g., poly(styrene)-b-poly(ethylene oxide) (PS-b-PEO)), or a triblock copolymer (e.g., PEO-b-PS-b-PEO)) (i.e. PS PEO block copolymers)).
- PS-b-PEO poly(styrene)-b-poly(ethylene oxide)
- PEO-b-PS-b-PEO triblock copolymer
- An "amphiphilic" copolymer is one containing both hydrophilic (water-soluble) and hydrophobic
- non-biodegradable 3 means non-hydroiysable in gastrointestinal conditions
- the hydrophobic uncharged non-biodegradable polymer used in copolymers of the present invention is a poly(ethylethylene) (-(CH 2 -CH(C 2 H5)) R -, i.e. or a poly(styrene) (- (CH 2 -CH(Ph)) n -, i.e. -(CH2-CH(C6H 5 )) n -, i.e. -(C 8 H 8 )n-).
- the hydrophobic uncharged nonbiodegradable polymer is a poly(styrene).
- Poly(styrenes) for use in the present invention may include non-substituted and/or substituted/functionalized styrene monomers.
- poly(styrene) is therefore used herein generically to designate a poly(styrene) that comprises exclusively non-substituted styrene monomers, a mix of substituted and non-substituted monomers or exclusively substituted monomers.
- the one or more substituents on the styrene monomer may include substituents on the phenyl and/or on the carbon on which the phenyl is attached and/or may form polycyclic derivatives with the phenyl (e.g., bicycles, tricycles, etc. comprising C3-C6 aryl(s) and/or C3-C6 cycloalkyl(s)).
- substituents include alkyl (C1 to C7 (C1, C2, C3, C4, C5, C6 or C7, more specifically C1, C2 or C3), aryl (C3-C6), C3-C8 cycloalkyi, aryl-alkyl, acetoxyl, alkoxyl (methoxyl, ethoxyl, propanoxyl, butoxyl, etc.), halogen (Br, CI, F, etc.), amine, amide, alkylamine, NO2.
- the substituents may themselves be substituted.
- the substituted styrene monomer include acetoxystyrene, benshydrylstyrene, benzyloxy-methoxystyrene, bromostyrene (2-, 3-, 4- or alpha), chlorostyrene (2-, 3-, 4- or alpha), fluorostyrene (2-, 3-, 4- or alpha), ferf-butoxystyrene, ferf-butylstyrene, chloro-methylstyrene, diclhlorostyrene, diflurostyrene, dimethoxystyrene, dimethylstyrene, dimethylvinylbenzylamine, diphenyl methyl pentene, (diphenylphosphino)styrene, ethoxystyrene, isopropenylaniline, isopropenyl-a,a-dimethylbenzyl isocyanate, [N- (methylamin)-2-,
- the substituted styrene monomer is an alkylstyrene (e.g., methyl styrene) or a tert- butylstyrene.
- the PS comprises at least one substituted styrene monomer.
- the substituents may be non-ionic groups (e.g., methyl- or tert-butyl groups).
- the styrene monomers in the poly(styrene) are unsubstituted.
- Hydrophilic uncharged and non-biodegradable polymer that can be used with poly(styrene) in the block copolymer of the present invention include polyethylene oxide), poly(N-vinylpyrrolidone), poly(ethyl oxazoline), poly(methyl oxazoline), and polymers of oligoethylene glycol alkyl acrylate.
- the hydrophilic uncharged and non-biodegradable polymer is polyethylene oxide).
- Polyethylene oxide) (PEO) for use in the present invention has the general formula:
- PEO polyethylene oxide
- the term "polyethylene oxide)" or PEO is therefore used herein generically to designate a PEO that comprises exclusively non-substituted ethylene oxide monomers, a mix of substituted and non-substituted monomers or exclusively substituted monomers.
- the PEO comprises at least one substituted ethylene oxide monomer.
- the ethylene oxide monomers are unsubstituted.
- the molecular weights of the PS and PEO blocks e.g., diblock PS-b-PEO or triblock PEO-b-PS-b-
- PS/PEO number average molecular weight ratio higher than 1.0 and lower than 4 (see e.g., Examples 6-13).
- the ratio is about 1.1 or higher and lower than 4.
- the ratio is about 1.2 or higher and lower than 4.
- the ratio is about 1.3 or higher and lower than 4.
- the ratio is about 1.4 or higher and lower than 4.
- the ratio is higher than 1 and about 3.9 or lower. In a specific embodiment, the ratio is about 1.1 or higher and lower than 3.9.
- the ratio is about 1.2 or higher and lower than 3.9. In another specific embodiment, the ratio is about 1.3 or higher and lower than 3.9. In another specific embodiment, the ratio is about 1.4 or higher and lower than 3.9. In another specific embodiment, the ratio is higher than 1 and about 3.8 or lower. In a specific embodiment, the ratio is about 1.1 or higher and lower than 3.8. In another specific embodiment, the ratio is about 1.2 or higher and lower than 3.8. In another specific embodiment, the ratio is about 1.3 or higher and lower than 3.8. In another specific embodiment, the ratio is about 1.4 or higher and lower than 3.8. In another specific embodiment, the ratio is higher than 1 and about 3.7 or lower. In a specific embodiment, the ratio is about 1.1 or higher and lower than 3.7.
- the ratio is about 1.2 or higher and lower than 3.7. In another specific embodiment, the ratio is about 1.3 or higher and lower than 3.7. In another specific embodiment, the ratio is about 1.4 or higher and lower than 3.7. In another specific embodiment, the ratio is higher than 1 and about 3.6 or lower. In a specific embodiment, the ratio is about 1.1 or higher and lower than 3.6. In another specific embodiment, the ratio is about 1.2 or higher and lower than 3.6. In another specific embodiment, the ratio is about 1.3 or higher and lower than 3.6. In another specific embodiment, the ratio is about 1.4 or higher and lower than 3.6. In another specific embodiment, the ratio is higher than 1 and about 3.5 or lower. In a specific embodiment, the ratio is about 1.1 or higher and lower than 3.5. In another specific embodiment, the ratio is about 1.2 or higher and lower than 3.5. In another specific embodiment, the ratio is about
- the ratio is about 1.4 or higher and lower than 3.5. In another specific embodiment, the ratio is about 1.4 or higher and lower than 3.5. In another specific embodiment, the ratio is higher than 1 and about 3.4 or lower. In a specific embodiment, the ratio is about 1.1 or higher and lower than 3.4. In another specific embodiment, the ratio is about 1.2 or higher and lower than 3.4. In another specific embodiment, the ratio is about 1.3 or higher and lower than 3.4. In another specific embodiment, the ratio is about 1.4 or higher and lower than 3.4. In another specific embodiment, the ratio is higher than 1 and about 3.3 or lower. In a specific embodiment, the ratio is about 1.1 or higher and lower than 3.3. In another specific embodiment, the ratio is about 1.2 or higher and lower than 3.3.
- the ratio is about 1.3 or higher and lower than 3.3. In another specific embodiment, the ratio is about 1.4 or higher and lower than 3.3. In another specific embodiment, the ratio is higher than 1 and about 3.2 or lower. In a specific embodiment, the ratio is about 1.1 or higher and lower than 3.2. In another specific embodiment, the ratio is about 1.2 or higher and lower than 3.2. In another specific embodiment, the ratio is about 1.3 or higher and lower than 3.2. In another specific embodiment, the ratio is about 1.4 or higher and lower than 3.2. In another specific embodiment, the ratio is higher than 1 and about 3.2 or lower. In a specific embodiment, the ratio is about 1.1 or higher and lower than 3.1. In another specific embodiment, the ratio is about 1.2 or higher and lower than 3.1. In another specific embodiment, the ratio is about 1.3 or higher and lower than 3.1. In another specific embodiment, the ratio is about 1.3 or higher and lower than 3.1. In another specific embodiment, the ratio is about 1.3 or higher and lower than 3.1. In another specific embodiment, the ratio is about 1.3 or
- the ratio is about 1.1 or higher and lower than 3. In another specific embodiment, the ratio is about 1.2 or higher and lower than 3. In another specific embodiment, the ratio is about 1.3 or higher and lower than 3. In another specific embodiment, the ratio is about 1.4 or higher and lower than 3. In another specific embodiment, the ratio is higher than 1 and about 2.9 or lower. In another specific embodiment, the ratio is about 1.1 or higher and about 2.9 or lower. In another specific embodiment, the ratio is about 1.2 or higher and about 2.9 or lower. In another specific embodiment, the ratio is about 1.3 or higher and about 2.9 or lower. In another specific embodiment, the ratio is about 1.4 or higher and about 2.9 or lower.
- the ratio is higher than 1 and about 2.8 or lower. In another specific embodiment, the ratio is about 1.1 or higher and about 2.8 or lower. In another specific embodiment, the ratio is about 1.2 or higher and about 2.8 or lower. In another specific embodiment, the ratio is about 1.3 or higher and about 2.8 or lower. In another specific embodiment, the ratio is about 1.4 or higher and about 2.8 or lower. In another specific embodiment, the ratio is higher than 1 and about 2.7 or lower. In another specific embodiment, the ratio is higher than about 1.1 and about 2.7 or lower. In a specific embodiment, the ratio is between about 1.2 and about 2.7 or lower. In a specific embodiment, the ratio is about 1.3 or higher and about 2.7 or lower.
- the ratio is about 1.4 or higher and about 2.7 or lower. In another specific embodiment, the ratio is higher than 1 and about 2.6 or lower. In another specific embodiment, the ratio is higher than about 1.1 and about 2.6 or lower. In a specific embodiment, the ratio is between about 1.2 and about 2.6 or lower. In a specific embodiment, the ratio is about 1.3 or higher and about 2.6 or lower. In a specific embodiment, the ratio is about 1.4 or higher and about 2.6 or lower. In another specific embodiment, the ratio is higher than 1 and about 2.5 or lower. In another specific embodiment, the ratio is higher than about 1.1 and about 2.5 or lower. In a specific embodiment, the ratio is between about 1.2 and about 2.5 or lower.
- the ratio is about 1.3 or higher and about 2.5 or lower. In a specific embodiment, the ratio is about 1.4 or higher and about 2.5 or lower. In another specific embodiment, the ratio is higher than 1 and about 2.4 or lower. In another specific embodiment, the ratio is higher than about 1.1 and about 2.4 or lower. In a specific embodiment, the ratio is between about 1.2 and about 2.4 or lower. In a specific embodiment, the ratio is about 1.3 or higher and about 2.4 or lower. In a specific embodiment, the ratio is about 1.4 or higher and about 2.4 or lower. In another specific embodiment, the ratio is higher than 1 and about 2.3 or lower. In another specific embodiment, the ratio is higher than about 1.1 and about 2.3 or lower.
- the ratio is between about 1.2 and about 2.3 or lower. In a specific embodiment, the ratio is about 1.3 or higher and about 2.3 or lower. In a specific embodiment, the ratio is about 1.4 or higher and about 2.3 or lower. In another specific embodiment, the ratio is higher than 1 and about 2.2 or lower. In another specific embodiment, the ratio is higher than about 1.1 and about 2.2 or lower. In a specific embodiment, the ratio is between about 1.2 and about 2.2 or lower. In a specific embodiment, the ratio is about 1.3 or higher and about 2.2 or lower. In a specific embodiment, the ratio is about 1.4 or higher and about 2.2 or lower. In another specific embodiment, the ratio is higher than 1 and about 2.1 or lower.
- the ratio is higher than about 1.1 and about 2.1 or lower. In a specific embodiment, the ratio is between about 1.2 and about 2.1 or lower. In a specific embodiment, the ratio is about 1.3 or higher and about 2.1 or lower. In a specific embodiment, the ratio is about 1.4 or higher and about 2.1 or lower. In another specific embodiment, the ratio is higher than 1 and about 2.0 or lower. In another specific embodiment, the ratio is higher than about 1.1 and about 2.0 or lower. In a specific embodiment, the ratio is between about 1.2 and about 2.0 or lower. In a specific embodiment, the ratio is about 1.3 or higher and about 2.0 or lower. In a specific embodiment, the ratio is about 1.4 or higher and about 2.0 or lower.
- PEOs having a molecular weight of between about 400 g/mol up to 20,000 g/mol are encompassed by the present invention.
- Applicants have no reason to expect that higher molecular weight PEO could not be effectively used in the present inventions. Polymers of smaller weight may be easier to manipulate.
- the PEO molecular weight is between 1000 and 5000 g/mol.
- the PS molecular weight is selected to satisfy the above described ratio. In accordance with the present invention, when the PEO has a molecular weight of about e.g., 20,000 g/mol, the PS molecular weight is lower than about 60,000 g/mol.
- polymersomes made of hydrophobic uncharged non-biodegradable polymer + hydrophilic uncharged non-biodegradable polymer di- or triblock copolymers (e.g., PS- ⁇ - ⁇ or PEO-b-PS- ⁇ - ⁇ copolymers))
- the strong interaction of the highly hydrophobic polymer e.g., aromatic (e.g., PS) with the capacity to make pi stacking interactions
- the highly hydrophobic polymer e.g., aromatic (e.g., PS)
- the capacity to make pi stacking interactions in the vesicle membrane provides resistance against gastrointestinal fluids and excipients comprised in topical formulations such as oils and surfactants.
- vesicles made of lipids (liposomes) or other amphiphilic diblock copolymers such as poly(butadiene)-b-poly(ethylene oxide) (PBD-b-PEO, also known as poly(butadiene)-b-poly(ethylene glycol), PBD-b- PEG; and poly(2-methyloxazoline)-0-poly(dimethylsiloxane)-0-poly(2-methyloxazoline), PMOXA-b-PDMS-b-PMOXA) are unable to take up ammonia in simple buffers (see e.g., Example 3), or are able to take up ammonia in simple buffers but lose their sequestering properties in media mimicking the intestinal fluids (see e.g., Examples 1 and 2).
- PPD-b-PEO poly(butadiene)-b-poly(ethylene oxide)
- PBD-b- PEG poly(2-methyloxazoline)-0-poly(dimethyl
- Copolymers used in the Examples described herein were purchased from Advanced Polymer Materials Inc (PS-b-PEO and PMOXA-b-PDMS-b- PMOXA) and Polymer Source Inc (PBD-b-PEO).
- the copolymer is dissolved in an organic solvent to form an organic phase, and the latter is mixed with the aqueous acidic solution (e.g., citric acid) (aqueous phase).
- aqueous acidic solution e.g., citric acid
- the mixing step may be performed through different techniques. For instance, an oil in water (o/w) emulsion (i.e. polymer-containing organic solvent phase (i.e. oil phase) in acidic aqueous solution (i.e. water phase)), a reverse-phase evaporation, a nanoprecipitation, or a double emulsion method, may be used to mix the polymer- containing organic phase and the aqueous phase.
- an oil in water (o/w) emulsion i.e. polymer-containing organic solvent phase (i.e. oil phase) in acidic aqueous solution (i.e. water phase)
- a reverse-phase evaporation i.e. water phase
- the polymer-containing organic solvent is mixed with the aqueous acidic phase under sonication for a time and time sufficient to form an emulsion.
- the aqueous phase was saturated with organic solvent under stirring for 30 minutes prior to the addition of the polymer-containing organic solvent phase.
- the polymer-containing organic solvent phase was added to the acid- containing aqueous phase under sonication for 3 minutes in an ice bath (to reduce the heat produced by the sonicator), using the following machine-specific parameters: amplitude 70, cycle 0.75 (UP200H, 200W, 24 kHz, Hielscher Ultrasound Technology).
- emulsion does not need to be stable in the methods of preparation of the present invention.
- a two-phase system comprising of a polymer- containing organic solvent and an acid-containing aqueous phase is sonicated, forming a water-in-oil (w/o) emulsion.
- the outer phase is evaporated under reduced pressure until a viscous gel-like state is formed. Polymersomes form upon the collapse of the gel state (Szoka and Papahadjopoulos. PNAS 1978; 75:4194-4198).
- the polymers are dissolved in a suitable organic solvent, to which acid-containing water is slowly added.
- polymersomes form in a w/o/w double emulsion containing an acid- containing aqueous inner phase, a polymer-containing completely or partially water immiscible organic solvent in the middle phase, and an aqueous outer phase.
- the organic solvent is then removed from the polymersome using any known technique. The solvent is removed prior to administration to avoid detrimental solvent ingestion or skin exposure by the subject. Without being so limited an application of lower than ambient pressure, heat, filtration, cross-flow filtration, dialysis, or a combination of these methods may be used to remove the solvent.
- the polymersomes can be used as is (with aqueous acid solution outside and inside the polymersomes), purified to change the composition of the non-encapsulated medium and/or further dried by conventional pharmaceutical drying procedures (e.g., freeze drying, spray drying).
- the drying step would allow the preparation of a solid dosage form (powder or capsules or tablet), which is easier to store and transport.
- the dried polymersomes could then be dispersed again in an aqueous medium (e.g., water, juice) or taken as is by the patient (e.g., capsule, tablet).
- the polymersomes When the polymersomes are meant to be topically administered, the polymersomes can be dispersed in any relevant topical formulation such as an aqueous solution, gel, foam or an emulsion such as lotion or cream. In all such forms (as is, purified and/or dried), the polymersome core contains acid. This acid provides the transmembrane pH gradient to the polymersome when it is within the gastrointestinal tract or in the formulation on the skin.
- the so formed polymersomes of the present invention contain acid, potentially salt (i.e., partially deprotonated acid with counterion such as sodium, potassium or calcium) which may be added during the polymersome preparation to adjust the pH and/or osmolarity in the core, and, in their hydrated form, polymersomes further contain water.
- acid potentially salt (i.e., partially deprotonated acid with counterion such as sodium, potassium or calcium) which may be added during the polymersome preparation to adjust the pH and/or osmolarity in the core, and, in their hydrated form, polymersomes further contain water.
- the pH in their core is generally between about 1 and 6 (1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6). In a specific embodiment, it is between about 1 and about 5, between about 1 and about 4.5, between about 1 and about 4, between about 1.5 and about 5, between about 1.5 and about 4.5, between about 1.5 and about 4, between about 2 and about 5, between about 2 and about 4.5, between about 2 and about 4, between about 2.5 and about 5, between about 2.5 and about 4.5, between about 2.5 and about 4, between about 3 and about 5, between about 3 and about 4.5, and between about 3 and about 5.
- polystyrene Although it is not necessary for the stability of the polymersomes of the present invention, they can also be crosslinked.
- a Friedel-Crafts reaction with the crosslinking agent p-xylylene-dichloride, 1 ,4- bis-chloromethyldiphenyl, monochlorodimethyl ether, dimethylformal, tris-(chloromethyl)-mesitylene, or p,p'-bis- chloromethyl-l,4-diphenylbutane may be used to crosslink poly(styrene) (Davankov and Tsyurupa, Reactive Polymers 1990; 13:27-42).
- the solvent used in the present invention dissolves the copolymer, and the polymer-containing solvent is then mixed with the acidic aqueous phase. During the mixing step (e.g., o/w emulsion), a fine dispersion of the polymer is formed in the aqueous phase. After the mixing step, the solvent is removed (e.g., evaporated) to ensure that the patients/subjects do not ingest it.
- the mixing step e.g., o/w emulsion
- the solvent is removed (e.g., evaporated) to ensure that the patients/subjects do not ingest it.
- a concentration of about 2% to about 40% (v/v) solvent phase/aqueous phase ratio may be used.
- the solvent phase/aqueous phase ratio is of about 5% to 30% (v/v).
- the solvent phase/aqueous phase ratio is of about 5% to 20% (v/v).
- the solvent phase/aqueous phase ratio is of about 5% to 15% (v/v).
- the solvent phase/aqueous phase ratio is of about 10% (v/v).
- the solvent phase/aqueous phase ratio in the resulting emulsion is about 9% (v/v).
- the solvent is an organic solvent.
- the solvent may be a chlorinated solvent (e.g., dichloromethane see e.g.,
- arene or arene derivative e.g., toluene, see e.g., Ex. 6
- aliphatic solvent or aliphatic solvent derivative e.g., hexane, 1-hexanol
- ketone or ketone derivative e.g., 2-hexanone
- ether or ether derivative e.g., diethylether
- mixtures thereof e.g., when using an o/w emulsion, w/o/w double emulsion or reverse-phase evaporation technique.
- solvents useful for the present invention are water immiscible or partially water immiscible organic solvents.
- solvents include e.g., dichloromethane see e.g., Ex. 5-6, 8-10, 12; or chloroform, see e.g., Ex. 7), arene or arene derivative (e.g., toluene, see e.g., Ex.
- aliphatic solvent or aliphatic solvent derivative e.g., hexane, 1-hexanol
- ketone or ketone derivative e.g., 2-hexanone
- ether or ether derivative e.g., diethylether
- the acidic solution at the core of the poiymersome preferably has a high buffering capacity at low pH for a high retention of basic compounds (e.g., ammonia, TMA, DMA).
- the acid is not toxic to animals, and does not (or only weakly) permeate out of the poiymersome membrane.
- the acid enclosed in the poiymersome core is (i) a hydroxy acid such as citric acid, isocitric acid, malic acid, tartaric acid, or lactic acid; (ii) a small chain fatty acid such as acetic acid; (iii) a sugar acid such as uronic acid; (iv) a dicarboxyiic acid such as malonic acid; (v) a tricarboxylic acid such as propane- 1 ,2,3-iriearboxyiic acid or aconitic acid; (vi) a tetracarboxy!ic acid such as 1 ,2,3,4-butanetetracarboxylic acid; (vii) a pentacarboxylic acid such as 1 ,2,3,4,5-pentanepentacarboxyiic acid; ( v iii) a polymeric po!y(carboxyiic acid) such as poly(acryiic acid) or poiy
- the citric acid is used.
- the encapsulated acid used in the poiymersome of the present invention Is not aimed at exerting a direct pharmacological or imaging function but is solely used to create the transmembrane pH gradient.
- the present invention encompasses the use of any one of the above-cited acids, whether or not they also possess certain pharmacological activities,
- the acid may not be an acid, other than any of the above- listed acids, that is known as an antibiotic, anticancer drug, an antihypertensive drug, an antifungal drug, an anxiolytic drug, an anti-inflammatory drug, an immunomodulatory drug, an antiviral drug, or a lipid lowering agent.
- the concentration of acid used in the method may be varied between 50 and 700 mM.
- a citric acid solution of between about 100 rniv! and 600 m at an osmolality between 50 and 800 mOsmoi/kg is optimally used (see FIG, 12).
- the osmolality is between 100 and 750 mOsmol/kg.
- the osmolality is between 100 and 700 rnQsmo!/kg.
- the osmolality is between 115 and 700 rnOsmol/kg,
- the acid within the core is present in a concentration that produces a pH between 1 and 6, when the polymersome is hydrated.
- Transmembrane pH-gradient polymersomes of the present invention may be used in the enteral
- ammonia or its methylated analog related disease or disorder e.g., oral, intracolonic, rectal
- topical treatment of an ammonia or its methylated analog related disease or disorder, or symptom thereof e.g. hyperammonemia (enteral) or trimethylaminuria (enteral or topical)
- an ammonia or its methylated analog related disease or disorder e.g. hyperammonemia (enteral) or trimethylaminuria (enteral or topical)
- an "ammonia or ammonia methylated analog-associated disease or disorder, or a symptom thereof” includes hyperammonemia (e.g., induced by impaired liver function), hepatic encephalopathy, liver cirrhosis, acute liver failure, acute-on-chronic liver failure, portosystemic bypass, portosystemic shunting, drug- induced hyperammonemia, inborn deficiency in hepatic ammonia metabolism (primary hyperammonemia), inborn deficiency affecting hepatic ammonia metabolism (secondary hyperammonemia), trimethylaminuria, a TMA- associated cardiovascular disease (e.g., atherosclerosis, peripheral artery disease, coronary artery disease, myocardial infarction), a TMA-associated kidney disease (e.g., renal tubulointerstitial fibrosis and dysfunction, renal insufficiency, chronic kidney disease-associated mortality) or TMA-associated bacterial vaginosis, or a
- the polymersomes may be administered enterally to the subject in different dosage forms e.g., could be dispersed in an aqueous medium (e.g., water, juice) or taken in their dried form as is by the subject (e.g., capsule, tablet).
- the polymersomes will be excreted via the feces.
- the polymersomes may also be administered topically to the subject in different dosage forms e.g., could be dispersed in a topical formulation such as an aqueous solution, a foam, a gel, or an emulsion (e.g., o/w or w/o) (e.g., lotion, cream).
- the terms "subject” or “subject in need thereof” refer to a subject who would benefit from receiving an effective amount of the polymersomes or composition thereof of the present invention. It refers to an animal, mammal and to a human in a specific embodiment.
- the compositions of the present invention may also be used for veterinary applications and be used in pets or other animals (e.g., pets such as cats, dogs, horses, etc.; and cattle, fishes, swine, poultry, etc.).
- the subject suffers from hyperammonemia (e.g., induced by impaired liver function).
- the subject suffers from hepatic encephalopathy, liver cirrhosis, acute liver failure, acute-on-chronic liver failure, portosystemic bypass, portosystemic shunting, drug- induced hyperammonemia, inborn deficiencies in hepatic ammonia metabolism (primary hyperammonemia), or inborn deficiencies affecting hepatic ammonia metabolism (secondary hyperammonemia), or any symptom thereof.
- the subject suffers from trimethylaminuria, a TMA-associated cardiovascular disease, a TMA-associated kidney disease, a TMA-associated bacterial vaginosis, or any symptom thereof.
- the polymersomes of the present invention may be stored as a liquid (e.g., liquid suspension), semi solid (e.g., emulsion such as lotion or cream) or solid form (e.g., powder, capsule, tablet, suppository).
- a liquid e.g., liquid suspension
- semi solid e.g., emulsion such as lotion or cream
- solid form e.g., powder, capsule, tablet, suppository
- the present invention also relates to the use of the polymersomes and/or compositions in the preparation of a medicament.
- the present invention also relates to pharmaceutical compositions comprising the above polymersomes of the invention.
- the polymersomes or compositions thereof of the invention may be administered through an enteral route (i.e. through the gastrointestinal tract) or topical route.
- the polymersomes can be in the form of e.g., tablets, coated tablets, hard or soft gelatin capsules or suspensions.
- the polymersomes can be in the form of e.g., suppositories or suspensions.
- the polymersomes can be in the form of an emulsion (e.g., o/w or w/o) such as a lotion or cream, gels and foams, or an aqueous solution.
- compositions of the invention can contain a pharmaceutically acceptable carrier including, without limitation, aqueous or non-aqueous solutions.
- a pharmaceutically acceptable carrier including, without limitation, aqueous or non-aqueous solutions.
- non-aqueous solvents include, without limitation, propylene glycol, polyethylene glycol, emulsions, etc.
- Aqueous carriers include, without limitation, water, alcohol, saline, and buffered solutions.
- Pharmaceutically acceptable carriers also can include physiologically acceptable aqueous vehicles (e.g., sugar solutions, saline) or other known carriers appropriate for the enteral or topical routes.
- the polymersomes of the present invention may be admixed with any known pharmaceutically inert, inorganic or organic excipient and/or carrier.
- suitable excipients/carriers include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof.
- excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose.
- the polymersomes of the present invention may be admixed with any known pharmaceutically inert, inorganic or organic excipient and/or carrier.
- suitable excipients/carriers include water, surfactants (e.g., polysorbates, sorbitan esters, sodium lauryl sulfate, etc.), oils (e.g., mineral or vegetable oils).
- compositions of the present invention may also contain preserving agents, stabilizing agents, wetting agents, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, or antioxidants. They may also contain other therapeutically active agents.
- compositions of the present invention are non-toxic and more generally pharmaceutically acceptable.
- pharmaceutically acceptable such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular composition of the present invention is administered.
- Polymersomes of the invention can also be administered in a combination therapy, i.e., combined with at least one other active agent or therapy for simultaneous or sequential administration.
- the combination therapy can include a polymersome or composition of the present invention combined with at least one other agent or therapy for the ammonia or its methylated analog-associated disease or disorder or symptom thereof.
- the combination therapy can include a polymersome or composition of the present invention combined with at least one other anti-hyperammonemia agent or therapy or with a medicament or therapy used for the prevention or treatment of at least one other symptom of a disease or condition of the subject having hyperammonemia.
- examples of active ingredients or therapies that may be administered in combination (simultaneously or sequentially) with the polymersomes or compositions of the present invention include lactulose, rifaximin, glycerol phenylbutyrate, lactitol, a branched-chain amino acid, neomycin, metronidazole, probiotic, a glutaminase inhibitor, L-ornithine-L-aspartate, hemodialysis, peritoneal dialysis, sodium phenylbutyrate, sodium phenylacetate/sodium benzoate, or carglumic acid.
- the combination therapy can include a polymersome or composition of the present invention combined with at least one other anti-trimethylaminuria agent or therapy or with a medicament or therapy used for the prevention or treatment of at least one other symptom of a disease or condition of the subject having trimethylaminuria.
- active ingredients or therapies that may be administered in combination (simultaneously or sequentially) with the polymersomes or compositions of the present invention include certain orally applied antibiotics (e.g., neomycin, metronidazole), activated charcoal, acidic soap.
- kits comprising at least one type of polymersomes or compositions of the present invention and instructions for their use.
- the kit can further contain a least one additional reagent, or one or more additional types of polymersomes of the invention.
- Kits typically include a label indicating the intended use of the contents of the kit.
- the term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
- the kit may further comprise one or more container(s), reagent(s), administration device(s).
- the dosages in which the polymersomes or compositions thereof of the invention are administered will depend on many factors including the age, other medications taken by subject (e.g., for other diseases or conditions) and other clinically relevant factors.
- the amount of the polymersomes or compositions thereof of the invention contained within a single dose will be an amount that effectively treats the ammonia or its methylated analog associated disease or disorder or symptom thereof (e.g., hyperammonemia, trimethylaminuria) without inducing significant toxicity.
- the effective amount of the polymersomes or compositions thereof of the invention may also be measured directly. The effective amount may be given daily or weekly or fractions thereof.
- the dose of polymersomes of the present invention expressed in terms of mass of block copolymer ranges from about 1 mg up to about 500 mg per kg of body weight per day (e.g., 1 mg, 10 mg, 50 mg, 100 mg, or 250 mg/ kg of body weight per day). Dosages may be provided in either a single or multiple dosage regimen. For example, in some embodiments the effective amount may range from about 250 mg to about 500 mg per day, from about 500 mg to about 1000 mg per day, about 1 gram per day, about 2-12 grams per day, about 14 g to about 86 grams of the composition per week, etc.
- the present invention encompasses any combination of the herein-described block copolymers, or compositions comprising same, in the herein-described ratios, prepared using the herein-described solvent and acid or acid solutions using the above-described organic phase and water phase mixing techniques.
- Liposome preparation Liposomes composed of (i) 1 ,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1 ,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), (ii) cholesterol and (iii) 1 ,2-distearoyl-sn-glycero-3- phosphoethanol-amine-N-[methoxy(PEO)-2000] (DSPE-PEO) at 54:45:1 mol% were prepared by the film hydration method. Stock solutions of DPPC 36.7 mg/mL, DSPC 39.5 mg/mL, cholesterol 19.3 mg/mL, and DSPE-PEO 13.9 mg/mL were prepared in chloroform.
- DSPC liposomes 8.2 mg cholesterol, 20.2 mg DSPC, and 1.3 mg DSPE-PEO were added as chloroform stock solutions to a glass vial.
- DPPC liposomes 19.7 mg DPPC, 8.7 mg cholesterol, and 1.4 mg DSPE-PEO, were added as chloroform stock solutions to a glass vial.
- the organic solvent was subsequently removed by nitrogen flow for 2 h and storage under vacuum overnight.
- the liposomes encapsulate the citric acid solution of pH 2. At the end of the process, there is citric acid inside and outside the liposomes.
- Ammonia capture capacity _ , , ,. . , —
- EXAMPLE 2 In vitro ammonia uptake of PBD-jb-PEO polymersomes with a PBD/PEO number average Mw ratio approximately (i.e. rounded to one decimal place) 1.7 prepared by mixing the polymer-containing organic solvent phase with the aqueous acidic phase using dichloromethane as organic solvent
- PBD-b-PEO polymersomes were produced using an oil-in-water (o/w) emulsion method. More particularly, sixty mg of PBD-b-PEO (PBD/PEO number average molecular weight (Mw) ratio of approximately 1.7 (i.e., 2500 g/mol / 1500 g/mol), PBD(2500)-b-PEO(1500)) were dissolved in 100 ⁇ of dichloromethane.
- the polymer dichloromethane solution polymer-containing organic solvent phase, i.e.
- the organic solvent was evaporated using a rotary evaporator for at least 5 minutes at 40°C.
- the polymersomes encapsulate the citric acid solution of pH 2. At the end of the process, there is citric acid inside and outside the polymersomes.
- EXAMPLE 3 In vitro ammonia uptake of PMOXA-jb-PDMS-jb-PMOXA polymersomes with a PDMS/PMOXA number average Mw ratio of approximately 2.4 prepared by mixing the polymer-containing organic solvent phase with the aqueous acidic phase using dichloromethane as organic solvent.
- PMOXA-b-PDMS-b-PMOXA polymersomes (PDMS/PMOXA number average Mw ratio of approximately 2.4 (PMOXA(520)-b-PDMS(2530)-b-PMOXA(520))) were produced as described in Example 2.
- EXAMPLE 4 In vitro ammonia uptake of PS-jb-PEO polymersomes with PS/PEO number average Mw ratios of approximately 1.3 or 2.5 prepared using a film hydration method.
- PS-b-PEO polymersomes were produced using a film hydration method. More particularly, 29.8 mg PS-b-PEO (PS/PEO number average Mw ratios of approximately 1.3 (PS(2600)- b-PEO(2000)) or of approximately 2.5 (PS(5150)-b-PEO(2060))) were dissolved in 100 ⁇ _ of dichloromethane and added to a glass vial. The organic solvent was subsequently removed by nitrogen flow for 2 h and storage under vacuum overnight. The dried film was hydrated with 1 ml_ of citric acid solution 250 mM at pH 2.0 at 300 mOsmol/kg under heating to 65°C and sonication for 1.25 h.
- PS-b-PEO polymersomes PS/PEO number average Mw ratio of approximately 1.0 (PS(1970)-b-PEO(2000)) were produced as described in Example 2.
- EXAMPLE 6 In vitro ammonia uptake at high bile salt concentrations of PS-jb-PEO polymersomes with PS/PEO number average Mw ratios between approximately 1.3 and 2.8 prepared by mixing the polymer- containing organic solvent phase with the aqueous acidic phase using dichloromethane or toluene as organic solvent
- PS-b-PEO polymersomes PS/PEO number average Mw ratios of approximately 1.3 (PS(2600)-b-PEO(2000)), approximately 1.6 (PS(3150)- >PEO(2000)), approximately 1.8 (PS(3570)-b-PEO(2000)), approximately 2.0 (PS(3900)-b-PEO(2000)), or approximately 2.5 (PS(5150)- > PEO(2060))) were produced as described in Example 2.
- PS PEO polymersomes (PS/PEO number average Mw ratio of approximately 2.8 (PS(6000)-b-PEO(2180))) were prepared as described in Example 2 but using toluene instead of dichloromethane as an organic solvent, and using a lower polymer amount (twenty mg).
- PS PEO polymersomes with a PS/PEO number average Mw ratio of approximately 1.3 to 2.5.
- PS PEO polymersomes PS/PEO number average Mw ratio of approximately 2.8 (PS(6000)-b-PEO(2180)) were evaluated as described in Example 5 with a modified phosphate concentration (25 mM) at 440 mOsmol/kg and pH 6.8.
- the PS PEO polymersomes were capable of capturing ammonia in bile salt-containing medium
- EXAMPLE 7 In vitro ammonia uptake at high bile salt concentrations of PS-jb-PEO polymersomes with a PS/PEO number average Mw ratio of approximately 3.8 prepared by mixing the polymer-containing organic solvent phase with the aqueous acidic phase using dichloromethane as organic solvent.
- PS-b-PEO was synthesized by atom transfer radical polymerization (ATRP).
- the reaction was conducted at 115 °C for 24 hours. Purification of the final product was achieved by passing the solution through a column of basic alumina, followed by two precipitations in hexane. The number average molecular weight of the polymer was determined by 1 H NMR spectroscopy, comparing the integral value of the PEG backbone to the aromatic polystyrene peaks, resulting in a polymer composition of PS(8100)-b-PEO(2150).
- PS-b-PEO polymersomes (PS/PEO number average Mw ratio of approximately 3.8 (PS(8100)-b-PEO(2150))) were produced as described in Example 2.
- the PS PEO polymersomes were capable of capturing ammonia in bile salt-containing medium
- EXAMPLE 8 In vitro ammonia uptake at high bile salt concentrations of PS-jb-PEO polymersomes with a PS/PEO number average Mw ratio of approximately 1.3 prepared by mixing the polymer-containing organic solvent phase with the aqueous acidic phase using chloroform as organic solvent
- PS-b-PEO polymersomes PS/PEO number average Mw ratio of approximately 1.3 (PS(2600)-b-PEO(2000)) were produced as described in Example 2 using chloroform instead of dichloromethane as organic solvent.
- the PS PEO polymersomes were capable of capturing ammonia in bile salt-containing medium
- EXAMPLE 9 In vitro ammonia uptake in hypo- and hyperosmolar conditions of PS-jb-PEO polymersomes with PS/PEO number average Mw ratios of approximately 1.3 or 2.5 prepared by mixing the polymer- containing organic solvent phase with the aqueous acidic phase using dichloromethane as organic solvent
- PS-b-PEO polymersomes PS/PEO number average Mw ratios of approximately 1.3 (PS(2600)-b-PEO(2000)) or of approximately 2.5 (PS(5150)- >PEO(2060)) were produced as described in Example 2.
- EXAMPLE 10 In vitro ammonia uptake in the presence of digestive enzymes of PS-jb-PEO polymersomes with a PS/PEO number average Mw ratio of approximately 2.5 prepared by mixing the polymer-containing organic solvent phase with the aqueous acidic phase using dichloromethane as organic solvent
- PS-b-PEO polymersomes PS/PEO number average Mw ratio of approximately 2.5 (PS(5150)-b-PEO(2060)) were produced as described in Example 2.
- in vitro ammonia uptake was studied by means of side-by-side diffusion cells as described in Example 5 with a modified buffer at pH 6.8 and 300 mOsmol/kg (phosphate buffer 50 mM, SC 12.5 mM, SDC 12.5 mM, trypsin from porcine pancreas 1 mg/mL (approximately 10 000 units/mL), a- chymotrypsin from bovine pancreas (Type II) 1 mg/mL (approximately 40 units/mL), lipase from porcine pancreas (Type II) 3 mg/mL (approximately 300 units/mL)).
- phosphate buffer 50 mM, SC 12.5 mM, SDC 12.5 mM trypsin from porcine pancreas 1 mg/mL (approximately 10 000 units/mL)
- a- chymotrypsin from bovine pancreas Type II
- the activity of the enzymes corresponds to the protease and lipase activity in simulated intestinal fluid United States Pharmacopeia (USP 39 - NF 34).
- the lower bile salt concentration than that used in Example 5 was selected to ensure enzymatic activity, and the kinetics was limited to four hours to avoid interferences by degradation products of the digestive enzymes.
- EXAMPLE 11 In vitro ammonia uptake at high potassium concentrations of PS-jb-PEO polymersomes with a PS/PEO number average Mw ratio of approximately 1.3 prepared by mixing the polymer-containing organic solvent phase with the aqueous acidic phase using dichloromethane as organic solvent
- PS-b-PEO polymersomes PS/PEO number average Mw ratio of approximately 1.3 (PS(2600)-b-PEO(2000)) were produced as described in Example 2.
- EXAMPLE 12 In vitro ammonia uptake of PS-jb-PEO polymersomes with a PS/PEO number average Mw ratio of approximately 1.3 prepared by mixing the polymer-containing organic solvent phase with the aqueous acidic phase using dichloromethane as organic solvent and with varying concentrations of acid
- PS-b-PEO polymersomes (PS/PEO number average Mw ratio of approximately 1.3 (PS(2600)-b-PEO(2000))) were produced as described in Example 2 using citric acid solution 100 mM (115 mOsmol/kg), 200 mM (230 mOsmol/kg), 250 mM (300 mOsmol/kg), 300 mM (340 mOsmol/kg), 400 mM (460 mOsmol/kg), 500 mM (580 mOsmol/kg) or 600 mM (700 mOsmol/kg) at pH 2.0.
- EXAMPLE 13 In vitro TMA uptake at high bile salt concentrations and after pre-exposition to an O/W emulsion of PS-jb-PEO polymersomes with PS/PEO number average Mw ratios between approximately 1.4 and 2.0 prepared by mixing the polymer-containing organic solvent phase with the aqueous acidic phase using dichloromethane as organic solvent
- the polymer and the TMA concentrations within the diffusion cells were 1.75 mg/mL and 1.5 mM, respectively.
- aliquots of 40 ⁇ _ were taken from the polymersome-free compartment and the TMA concentration was determined by the PocketChemTM BA PA-4140 (Arkray Inc.) which was calibrated with TMA standards.
- the TMA capture capacity was quantified using equation 3 in which the total TMA concentration refers to the TMA amount in the cells at 10 minutes of incubation:
- the data show that the polymersomes efficiently captured TMA under harsh conditions mimicking the intestinal tract environment or after incorporation into an O/W emulsion (e.g., lotion or cream, for topical administration).
- Trimethylaminuria, fish odour syndrome a new method of detection and response to treatment with metronidazole. Journal of inherited metabolic disease, 18(3), 306-312.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Dispersion Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Neurology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16184371 | 2016-08-16 | ||
EP16200067 | 2016-11-22 | ||
EP16203817 | 2016-12-13 | ||
PCT/IB2017/054966 WO2018033856A1 (fr) | 2016-08-16 | 2017-08-15 | Polymersomes à gradient de ph transmembranaire et leur utilisation dans le piégeage de l'ammoniac et de ses analogues méthylés |
Publications (2)
Publication Number | Publication Date |
---|---|
EP3500311A1 true EP3500311A1 (fr) | 2019-06-26 |
EP3500311B1 EP3500311B1 (fr) | 2020-05-27 |
Family
ID=59738388
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17758637.7A Active EP3500311B1 (fr) | 2016-08-16 | 2017-08-15 | Polymersomes à gradient ph transmembranaire et leur utilisation dans le traitement de l'hyperammonémie |
Country Status (10)
Country | Link |
---|---|
US (1) | US11026891B2 (fr) |
EP (1) | EP3500311B1 (fr) |
JP (1) | JP7178090B2 (fr) |
KR (1) | KR102480918B1 (fr) |
CN (1) | CN109803685B (fr) |
AU (1) | AU2017314181B2 (fr) |
CA (1) | CA3026706C (fr) |
DK (1) | DK3500311T3 (fr) |
ES (1) | ES2812820T3 (fr) |
WO (1) | WO2018033856A1 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112924529A (zh) * | 2019-12-06 | 2021-06-08 | 中国科学院大连化学物理研究所 | 一种基于离子迁移谱仪的氧化三甲胺检测方法及其应用 |
IL302699A (en) | 2020-11-17 | 2023-07-01 | Genfit | Treatment methods for liver failure |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6916488B1 (en) | 1999-11-05 | 2005-07-12 | Biocure, Inc. | Amphiphilic polymeric vesicles |
US6835394B1 (en) | 1999-12-14 | 2004-12-28 | The Trustees Of The University Of Pennsylvania | Polymersomes and related encapsulating membranes |
US20050003016A1 (en) | 1999-12-14 | 2005-01-06 | Discher Dennis E. | Controlled release polymersomes |
US7682603B2 (en) | 2003-07-25 | 2010-03-23 | The Trustees Of The University Of Pennsylvania | Polymersomes incorporating highly emissive probes |
AU2006220816A1 (en) | 2005-03-04 | 2006-09-14 | President And Fellows Of Harvard College | Method and apparatus for forming multiple emulsions |
WO2007038763A1 (fr) | 2005-09-28 | 2007-04-05 | The Trustees Of The University Of Pennsylvania | Polymersomes biodegradables autoassembles |
US7347953B2 (en) | 2006-02-02 | 2008-03-25 | International Business Machines Corporation | Methods for forming improved self-assembled patterns of block copolymers |
EP2019691B1 (fr) | 2006-05-15 | 2020-08-12 | Massachusetts Institute of Technology | Polymères pour particules fonctionnelles |
US8486924B2 (en) | 2007-11-28 | 2013-07-16 | Celator Pharmaceuticals, Inc. | Taxane delivery system |
WO2009117188A2 (fr) | 2008-03-17 | 2009-09-24 | The Trustees Of The University Of Pennsylvania | Stabilisation de membranes macromoléculaires |
US20110195501A1 (en) | 2008-08-06 | 2011-08-11 | Pangu Gautam D | Ultrasonically induced release from polymer vesicles |
US8951571B2 (en) | 2008-09-26 | 2015-02-10 | The Trustees Of The University Of Pennsylvania | Polymer vesicles for selective electromagnetic energy-induced delivery |
WO2010148395A1 (fr) | 2009-06-19 | 2010-12-23 | The Trustees Of The University Of Pennsylvania | Polymérosomes poreux paramagnétiques et leurs utilisations |
WO2010148653A1 (fr) | 2009-06-26 | 2010-12-29 | Shanghai Jiao Tong University | Vésicules polymères de membrane asymétrique |
CN101792516B (zh) * | 2009-12-28 | 2012-05-23 | 苏州大学 | 生物可降解聚合物囊泡及其制备和应用 |
US8808748B2 (en) | 2010-04-20 | 2014-08-19 | Vindico NanoBio Technology Inc. | Biodegradable nanoparticles as novel hemoglobin-based oxygen carriers and methods of using the same |
CN103079642A (zh) | 2010-07-16 | 2013-05-01 | 丹麦科技大学 | 纳米颗粒引导的放射疗法 |
PT2661275T (pt) | 2011-01-07 | 2019-04-24 | Poseida Therapeutics Inc | Composições e métodos para a entrega a tumores de agentes ligantes de elevada afinidade para o oxigénio |
GB201106433D0 (en) | 2011-04-15 | 2011-06-01 | Reckitt & Colman Overseas | Composition and method |
US10221445B2 (en) * | 2011-08-11 | 2019-03-05 | Qiagen Gmbh | Cell- or virus simulating means comprising encapsulated marker molecules |
EP2744399B1 (fr) | 2011-08-15 | 2017-07-12 | University of Connecticut | Lutte contre l'encrassement biologique dans des biocapteurs implantables |
EP2695606A1 (fr) | 2012-08-09 | 2014-02-12 | ETH Zürich | Composition de liposomes destinée à la dialyse péritonéale |
WO2014130761A2 (fr) | 2013-02-22 | 2014-08-28 | President And Fellows Of Harvard College | Véhicules thérapeutiques actifs nanostructurés et leurs utilisations |
EP3039422B1 (fr) | 2013-08-30 | 2019-01-09 | University of Maryland, College Park | Dispositif et procédés d'utilisation du dispositif pour la détection de l'hyperammoniémie |
US9557337B2 (en) | 2013-10-02 | 2017-01-31 | Becton, Dickinson And Company | Polymersome encapsulation of hydrophobic fluorescent polymers |
GB201318787D0 (en) | 2013-10-24 | 2013-12-11 | Univ Leiden | Upconverting vehicles and uses |
CN104771382A (zh) | 2015-03-31 | 2015-07-15 | 中国医学科学院生物医学工程研究所 | 亲水性内腔载蒽环类药物的聚合物囊泡及制备方法及用途 |
-
2017
- 2017-08-15 CA CA3026706A patent/CA3026706C/fr active Active
- 2017-08-15 JP JP2018567213A patent/JP7178090B2/ja active Active
- 2017-08-15 AU AU2017314181A patent/AU2017314181B2/en active Active
- 2017-08-15 DK DK17758637.7T patent/DK3500311T3/da active
- 2017-08-15 ES ES17758637T patent/ES2812820T3/es active Active
- 2017-08-15 EP EP17758637.7A patent/EP3500311B1/fr active Active
- 2017-08-15 CN CN201780050110.0A patent/CN109803685B/zh active Active
- 2017-08-15 US US16/326,133 patent/US11026891B2/en active Active
- 2017-08-15 WO PCT/IB2017/054966 patent/WO2018033856A1/fr unknown
- 2017-08-15 KR KR1020187037076A patent/KR102480918B1/ko active IP Right Grant
Also Published As
Publication number | Publication date |
---|---|
AU2017314181A1 (en) | 2018-12-20 |
DK3500311T3 (da) | 2020-08-17 |
KR20190039674A (ko) | 2019-04-15 |
ES2812820T3 (es) | 2021-03-18 |
JP2019524668A (ja) | 2019-09-05 |
WO2018033856A1 (fr) | 2018-02-22 |
CN109803685A (zh) | 2019-05-24 |
CN109803685B (zh) | 2023-02-17 |
CA3026706A1 (fr) | 2018-02-22 |
JP7178090B2 (ja) | 2022-11-25 |
CA3026706C (fr) | 2024-01-09 |
EP3500311B1 (fr) | 2020-05-27 |
KR102480918B1 (ko) | 2022-12-23 |
US20190183800A1 (en) | 2019-06-20 |
US11026891B2 (en) | 2021-06-08 |
AU2017314181B2 (en) | 2022-12-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Frederick | Current concepts in the pathophysiology and management of hepatic encephalopathy | |
Matoori et al. | Recent advances in the treatment of hyperammonemia | |
Zheng et al. | An orally delivered microbial cocktail for the removal of nitrogenous metabolic waste in animal models of kidney failure | |
Evenepoel et al. | The gut–kidney axis | |
Hida et al. | Inhibition of the accumulation of uremic toxins in the blood and their precursors in the feces after oral administration of Lebenin®, a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis | |
US20040105895A1 (en) | Monovalent-selective cation exchangers as oral sorbent therapy | |
AU2017314181B2 (en) | Transmembrane pH-gradient polymersomes and their use in the scavenging of ammonia and its methylated analogs | |
Lu et al. | Nanoparticle-mediated delivery of emodin via colonic irrigation attenuates renal injury in 5/6 nephrectomized rats | |
Hoilat et al. | Evidence-based approach to management of hepatic encephalopathy in adults | |
WO2005065429A2 (fr) | Composition et procede de traitement de l'encephalopathie hepatique | |
Rahman et al. | Protective effect of activated charcoal against progression of chronic kidney disease: A randomized clinical study | |
CN104204082B (zh) | 高分子化氮氧化合物与无机颗粒的有机-无机杂合复合物 | |
KR20120030542A (ko) | 리팍시민에 대한 전신 노출의 조절 | |
Bertrand et al. | Designing polymeric binders for pharmaceutical applications | |
RU2318513C1 (ru) | Лекарственное средство на основе d-циклосерина, препарат пролонгированного действия, содержащий наночастицы, способ его получения | |
Matoori | Investigating poly (styrene)-b-poly (ethylene oxide) polymersomes for the treatment and diagnosis of hyperammonemia | |
JP2015536330A (ja) | トリメチルアミン−n−オキシドのレベルを下げる医薬組成物 | |
Schmidt | Transmembrane pH-gradient poly (isoprene)-block-poly (ethylene glycol) polymersomes in the detoxification of endogenous metabolites | |
AU2022338728A1 (en) | Artificial enzyme-bacteria system and uses thereof | |
Hainiuk et al. | REVIEW OF THE LITERATURE ON THE TOXIC EFFECT OF ALCOHOL ON THE BODY OF CURRENT METHODS OF TREATMENT OF ALCOHOL INTOXICATION | |
HONDA et al. | Effect of activated carbon beads on serum lipid levels and fecal bile acid excretion in rats | |
JP2024534721A (ja) | 人工酵素・細菌系及びその使用 | |
JP2022548788A (ja) | リファキシミン液体製剤 | |
Smith | Polymeric Chelators For Pharmaceutical Applications | |
WO2024073056A1 (fr) | Compositions de cucurbiturile, produits et procédés d'utilisation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20181128 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTG | Intention to grant announced |
Effective date: 20200227 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 1273851 Country of ref document: AT Kind code of ref document: T Effective date: 20200615 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602017017404 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: COSMOVICI INTELLECTUAL PROPERTY SARL, CH |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 Effective date: 20200810 Ref country code: NO Ref legal event code: T2 Effective date: 20200527 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: FP |
|
REG | Reference to a national code |
Ref country code: SE Ref legal event code: TRGR |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG4D |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200927 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200928 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200828 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200827 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 1273851 Country of ref document: AT Kind code of ref document: T Effective date: 20200527 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602017017404 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2812820 Country of ref document: ES Kind code of ref document: T3 Effective date: 20210318 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20200815 |
|
26N | No opposition filed |
Effective date: 20210302 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: MT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 |
|
P01 | Opt-out of the competence of the unified patent court (upc) registered |
Effective date: 20230421 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NO Payment date: 20230824 Year of fee payment: 7 Ref country code: IT Payment date: 20230825 Year of fee payment: 7 Ref country code: IE Payment date: 20230822 Year of fee payment: 7 Ref country code: GB Payment date: 20230822 Year of fee payment: 7 Ref country code: CH Payment date: 20230902 Year of fee payment: 7 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 20230821 Year of fee payment: 7 Ref country code: FR Payment date: 20230830 Year of fee payment: 7 Ref country code: DK Payment date: 20230823 Year of fee payment: 7 Ref country code: DE Payment date: 20230821 Year of fee payment: 7 Ref country code: BE Payment date: 20230821 Year of fee payment: 7 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20231027 Year of fee payment: 7 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20240726 Year of fee payment: 8 |